Optical genome mapping uncovers disease-defining variants in an adult T-lymphoblastic leukemia and impacts prognosis

Adult T-lymphoblastic leukemia often harbors cryptic structural variants that remain undetected by standard cytogenetic and targeted molecular testing, limiting precise risk stratification and therapeutic planning. This case is notable for the use of optical genome mapping (OGM) to uncover multiple disease-defining and likely oncogenic genomic alterations in an adult patient with newly diagnosed T-lymphoblastic leukemia. The report highlights how comprehensive structural variant profiling can refine prognosis and identify clinically meaningful aberrations that would otherwise be missed in routine practice.

A 29-year-old man presented with fever, chills, dyspnea, headache, petechiae, and was found to have pancytopenia. Bone marrow biopsy showed a hypercellular marrow with approximately 95% involvement by T-lymphoblasts and residual trilineage hematopoiesis. Flow cytometry demonstrated a T-lymphoblastic immunophenotype with expression of cytoplasmic CD3, CD7, terminal deoxynucleotidyl transferase (TdT), absent surface CD3, CD20, CD34, CD117, and myeloperoxidase. Conventional workup with fluorescence in situ hybridization (FISH) initially detected a CDKN2A loss but did not fully define prognosis. OGM revealed a deletion involving FBXW7, a TLX3::BCL11B fusion (subsequently confirmed by FISH), a hemizygous deletion involving PHF6, a duplication involving MYB, and a deletion involving CDKN2A, while next-generation sequencing identified a NOTCH1 missense variant at approximately 50% variant allele fraction. A normal male karyotype was detected at post-induction staging. The patient was counseled on the overall favorable prognostic markers and started on induction therapy using the AALL1231 regimen for T‑lymphoblastic leukemia, including protocol-directed incorporation of bortezomib.

OGM revealed multiple clinically relevant structural variants and partner genes impacted in adult T-lymphoblastic leukemia that were not part of the standard cytogenetic workup, thereby improving genomic characterization and risk assessment. Identification of alterations involving FBXW7, NOTCH1, TLX3::BCL11B, PHF6, MYB, and CDKN2A provided a comprehensive genomic profile that informed counseling regarding prognosis and supported treatment selection. Integrating OGM into routine evaluation of myeloid and lymphoid neoplasms has the potential to streamline diagnostic workflows and ensure that disease-defining aberrations critical for diagnosis, prognosis, and targeted therapy selection are not overlooked.